The ability to control an animal's date of birth is generally of importance in animal breeding. More particularly, the economic considerations surrounding the breeding of some species, e.g., thoroughbred race horses, have traditionally inspired creative scientific approaches to equine breeding. The ability to accurately and precisely select equine birth dates is especially important in light of the official determination, by the breeder's association, of January 1 as the universal birth date of thoroughbred horses for racing purposes. That is, all horses born within a calendar year are presumed to have a January 1 birth date for racing purposes. Thus, animals born earlier within any given calendar year have a significant developmental advantage over those born later in the same year. Accordingly, substantial research and development efforts have been directed at controlling the equine reproductive cycle in order to produce horses with actual birth dates on or shortly after January 1 and, thereby, augment the developmental state of thoroughbred horses.
Female horses experience estrous cycles about 21-23 days in length, with some seasonal variations, except for a period of about two to five months. During the latter period, the mare typically experiences an anestrous period, i.e. a period of sexual inactivity. This period commonly ranges in the northern hemisphere from about November to March (see, for example, The Horse, J. W. Evans, 2nd Ed., pp. 351-373, W. H. Freeman & Co. (1990)). However, since the gestation period of the mare is about 335-340 days, February is the ideal month for mare impregnation in order to achieve an early birth date in the following calendar year, i.e. in January or February. Since in the northern hemisphere mares typically go through their yearly anestrous period during these months, the onset of estrous to attain an early birth date must be induced artificially.
In the northern hemisphere, the largest number of mares experience ovulation during the longest daylight periods of June. The observation of this correlation between extended daylight periods and increased mare ovulation rates led to the management of equine breeding by "extending the photoperiod". Thus, ovulation has been induced during the anestrous period by placing mares under artificial lighting to, thereby, extend the perceived daylight period up to about 16 hours per day.
Both follicular development and the onset of ovulation are dependent on the presence of certain hormones, such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone (see, for example, D. Freeman et al., "Mare management", Large Animal Vet.: 6-8 (July/August, 1992)). The blood levels of these hormones vary in a relatively predictable manner during the normal female equine reproductive cycle. Ovulation has also been induced in a mare by delivery of pharmaceuticals which interfere with the hormonal cycle of the mare. Prostaglandin and its analogues, for example, have been delivered to mares to cause the regression of the corpus luteum, and to thereby attain a reduction of the estrous period. Progesterone has also been delivered to either suppress or synchronize the heat periods in mares having long and erratic estrous cycles.
LHRH (also known as gonadotropin releasing hormone or GnRH) and follicle-stimulating hormone (FSH) have been employed to alter the female equine reproductive cycle. LHRH has been delivered to equines by various methods, including injection and implantation. For instance, LHRH has been delivered by intravenous and intramuscular injection in order to determine its effect on the release of luteinizing hormone (LH) and ovulation (see, J. E. Turner, "The Effect of Various Gonadotropin-releasing Hormone Regimes on Gonadotrophins, Follicular Growth and Ovulation in Deeply Anoestrous Mares", J. Reprod. Fert. Suppl. 44:213-225 (1991)). LHRH has also been successfully delivered to mares from subcutaneously implanted osmotic minipumps, which are commercially available from ALZA Corporation, Palo Alto, Calif.) to induce ovulation (see, C. G. V. , Ainsworth, "Continuous Infusion of Gonadotropin-releasing Hormone (GnRH) Advances the Onset of Oestrous Cycles in Thoroughbred Mares on Australian Stud Farms", J. Reprod. Fert, Suppl 44:235-240 (1991)).
Although some induction of ovulation was attained in mares by injection and implantation of LHRH and its analogs, there are drawbacks associated with these delivery techniques. One important problem associated with injections is the pulsatile nature of the delivery, which typically cannot provide the desired uniformity of drug concentration in the bloodstream. Another problem with injecting LHRH is its short half life, requiring frequent injections to maintain LHRH plasma levels. Another problem associated with this, and other non-continuous delivery systems, is that they require repeated human intervention by highly trained personnel to administer injections on a regular basis. On the other hand, implantation techniques have unique problems associated with the surgical procedure required for the subcutaneous insertion of the device. These problems require sterilization to prevent infections, which increase labor costs, and produce significant mare discomfort, which may cause rubbing or scratching at the implantation site.
As used herein, the term "electrotransport", refers generally to the passage of a substance through a body surface, such as skin, mucous membrane, or nails, induced at least partially by an electrical field. For example, a therapeutic agent may be introduced into an animal's body by one of several electrotransport processes. One form of electrotransport, called iontophoresis, involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the movement of a liquid and all agents, including uncharged agents, dissolved therein under the influence of an electric field. Still another type of electrotransport, electroporation, involves the transport of an agent through transiently-existing pores formed in the skin or other biological membranes by the application of an electric field. In any given electrotransport process, however, more than one of these processes may be occurring simultaneously to some extent. Accordingly, the term "electrotransport" is used herein in its broadest possible meaning, which includes the electrically induced or enhanced transport of at least one agent, which may be charged, or uncharged, or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent is actually transported.
Sibalis U.S. Pat. Nos. 5,013,293; 5,312,325 and 5,372,579 all disclose an electrolytic transdermal patch provided with a current oscillator for the periodic delivery of LHRH to induce or inhibit ovulation. The patent teaches delivering "pulses" of electrotransport current, each pulse being about 6 minutes in duration, at a frequency of one 6 minute pulse per hour, to deliver LHRH to women in order to match the body's natural release of LHRH and thereby induce ovulation. However, the delivery of LHRH at a frequency of two or more 6 minute pulses per hour is said to completely extinguish gonadotrophic secretion and inhibit ovulation (see, column 2, lines 44-57 and column 6, lines 16-30 of Sibalis U.S. Pat. No. 5,013,293).
There is still a need for an effective method of non-invasively delivering LHRH, or an analog thereof, to successfully attain scheduled ovulation, insemination and/or pregnancy, particularly for breeding animals (e.g., cattle and horses) and more particularly for breeding animals having seasonal anestrous periods.